This proposal focuses on the development of a new therapeutic for systemic lupus erythematosus. The overall goal is to 1) modify a peptide mimetope of DNA to increase serum half life, permit oral administration, and maximize function, 2) to explore the functionality of two new compounds with similar binding properties to the peptide and 3) develop additional compounds. The mimetope binds to a subset of anti-DNA antibodies that deposit in glomeruli, cross-react with NMDA receptors and mediate excitotoxic neuron death, and, in immune complexes, activate dendritic cells. Efforts will be made to use radioisotope-tagged peptide/modified compound to ablate antigen-specific B cells. It will also be determined if peptide intercalates into DNA-containing immune complexes to diminish activation of dendritic cells. Finally, new peptide mimetopes of DNA will be sought in case more than one subset of anti-DNA antibodies or DNA-reactive B cells must be eliminated to reduce disease pathology. PUBLIC HEALTH RELEVANCE: This proposal identifies a non-immunosuppressive strategy for the treatment of systemic lupus.